EP1488209B1 - Mise en evidence d'un peptide partiel proadrenomedulline a region moyenne dans des liquides biologiques, a des fins diagnostiques et dosages immunologiques utilises pour effectuer une mise en evidence de ce type - Google Patents

Mise en evidence d'un peptide partiel proadrenomedulline a region moyenne dans des liquides biologiques, a des fins diagnostiques et dosages immunologiques utilises pour effectuer une mise en evidence de ce type Download PDF

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EP1488209B1
EP1488209B1 EP04700013A EP04700013A EP1488209B1 EP 1488209 B1 EP1488209 B1 EP 1488209B1 EP 04700013 A EP04700013 A EP 04700013A EP 04700013 A EP04700013 A EP 04700013A EP 1488209 B1 EP1488209 B1 EP 1488209B1
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proam
antibodies
mid
antibody
peptide
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EP1488209A1 (fr
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Andreas Bergmann
Joachim Struck
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BRAHMS GmbH
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54306—Solid-phase reaction mechanisms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/26—Infectious diseases, e.g. generalised sepsis

Definitions

  • the invention relates to methods for determining a midregionalen Partial peptide of proadrenomedullin (mid-proAM), in particular the determination of the proAM (45-92) partial peptide in biological fluids for medical diagnostic purposes, especially in sepsis diagnostics, but also e.g. in cancer diagnostics and cardiac diagnostics or generally in the context of the diagnosis of such disease states, where a determination of the peptide adrenomedullin (AM) provides diagnostically relevant results.
  • the invention Determinations are made in particular by means of Immunoassays of a type in which a labeled antibody working (sandwich assay, competitive assay after the SPALT or SPART principle).
  • diagnosis is used basically used as a simplifying generic term, the also prognosis / early prognosis and therapy-accompanying follow-up should include.
  • the peptide adrenomedullin (AM) was first introduced in 1993 as a new 52-amino acid hypotensive peptide derived from a human phenochromocytoma had been isolated from Kitamura et al. (cf 18, figures refer to the attached literature list). In the same year was also the for a precursor peptide of 185 amino acids coding cDNA and the complete amino acid sequence of this precursor peptide (19, SEQ ID NO: 1).
  • the Precursor peptide which i.a. a signal sequence of 21 amino acids at the N-terminus is termed "preproadrenomedullin" (pre-proAM).
  • pre-proAM preproadrenomedullin
  • All indicated amino acid positions are usually related to the 185 amino acid pre-proAM, the has the sequence according to SEQ ID NO: 1, unless it something else results from the concrete context of the text.
  • the peptide adrenomedullin is a 52 amino acid comprehensive Peptide (SEQ ID NO: 2) containing amino acids 95 to 146 of the pre-proAM, from which it is split by proteolytic cleavage is formed.
  • SEQ ID NO: 2 The peptide adrenomedullin
  • AM is an effective vasodilator, being the hypotensive Effect especially peptide sections in the C-terminal part can be assigned to the AM.
  • Peptide sequences from the N-terminus of AM show hypertensive effects (cf. (6)).
  • the concentrations of the AM which can be found in circulation and other biological Can measure fluids in a number of disease states significantly above that in healthy controls to be found concentrations. So are the AM mirrors in patients with congestive heart failure (congestive heart failure), myocardial infarction, kidney disease, high blood pressure, Diabetes mellitus, in the acute phase of a Shocks and in sepsis and septic shock significantly, albeit to varying degrees (see, e.g., (2), Chapter 7, and the literature cited). Also the PAMP concentrations are in some of the mentioned disease states increased, however, the plasma levels opposite AM are relatively low ((2), p.1702).
  • the pre-proAM (SEQ ID NO: 1) formed in which the amino acid sequences corresponding to these peptides present as partial peptides in equimolar amounts are measurable in biological fluids Concentrations of AM or PAMP appear to be different. That's nothing unusual. So can the measurable Concentrations of various degradation products one and the same Precursor peptides e.g. therefore be different because they are the result of different competing degradation pathways, the e.g. at different disease states to one different fragmentation of a precursor peptide and thus lead to various degradation products.
  • Certain im Precursor peptide-containing partial peptides can be used as free peptides are formed or not formed, and / or different peptides are used in different ways and formed in different quantities. Even if for processing a precursor peptide only a single degradation path trodden is, and thus all degradation products off and on originate from the same precursor peptide and primarily in equimolar quantities must have arisen, the in biological liquids measurable stationary concentrations different partial peptides and fragments very different be, namely e.g. then, if individual of them with different Speed are formed and / or in the respective biological fluid different individual Have stabilities (lifetimes), or if they are due to different clearance mechanisms and / or with different clearance speeds from the Circulation are removed.
  • WO00 / 69900 discloses a peptide (SEQ ID NO: 939) which corresponds to that of SEQ ID NO: 3 of the corresponds to this application. However, WO00 / 69900 does not disclose any diagnostic Application of this peptide.
  • the Applicant has therefore set itself the task, a to create a valid, routine-suitable measuring method, the opposite the o.g. Disturbing effects of a direct measurement of AM is largely insensitive and the reliable values for the physiological production of AM and / or its Precursors in various disease states, in particular Sepsis or other disease states in which elevated Values for AM can be found that can deliver.
  • Claim 1 represents the core of the present invention.
  • solid phase bound competitor served in the described SPALT assay the solid phase bound peptide (69-86: Peptide region SPCD19; SEQ ID NO: 4), as antibodies against this peptide formed and this peptide recognizing labeled anti-SPCD19 sheep antibody (affinity purified; see. Experimental part).
  • a solid phase bound competitor served in the described SPALT assay the solid phase bound peptide (69-86: Peptide region SPCD19; SEQ ID NO: 4), as antibodies against this peptide formed and this peptide recognizing labeled anti-SPCD19 sheep antibody (affinity purified; see. Experimental part).
  • Detection limit was about 50 pmol / l.
  • the method thus relates in particular to the determination of mid-proAM in the circulation of a patient, especially using plasma samples.
  • an assay format will be used preferred in which worked with labeled antibodies is, e.g. an assay following the one described above competitive split principle works (although also other markers, e.g. radioactive as a SPART assay, can be used).
  • non-competitive sandwich assays e.g. the way he deepens for the more in-depth Investigations was used and below will be described in more detail.
  • Non-Competitive Sandwich Immunoassays have a number of competitive immunoassays' of benefits that include being better than solid phase assays (heterogeneous assays) can be designed in the handling can be more robust, measuring results with can deliver a higher sensitivity and also better suitable for automation and series measurement. In addition, they can be compared with competitive immunoassays, who work with just one type of antibody, too provide additional statements by using sandwich immunoassays only recognize such molecules or peptides in which both Binding sites for those used for sandwiching Antibodies are present on the same molecule.
  • the antibodies can in principle be any suitable monoclonal and / or polyclonal antibodies, wherein however, currently affinity purified polyclonal antibodies to be favoured.
  • the antibodies by immunization an animal, especially sheep, with an antigen obtained containing a synthetic peptide sequence, the the amino acids 69-86 of the pre-proAM as well as an additional Having cysteine residue at the N-terminus (SEQ ID NO: 4).
  • the other Antibody can e.g. obtained in accordance with an antigen which contains a synthetic peptide sequence containing the Amino acids 83-94 (peptide region PSR13; SEQ ID NO: 5) of the pre-proAM with an additional cysteine residue at the N-terminus having.
  • Those using the mentioned synthetic Peptides that share a gapless midregional Capture section of the proAM sequence obtained antibodies recognize only binding sites in the area of o.g. mid-proAM (Amino acids 45-92), more specifically in the region of amino acids 60-92 of pre-proAM.
  • the method is described as heterogeneous sandwich immunoassay performed in which a the antibody to any solid phase, for example the walls of coated test tubes (e.g., polystyrene; "Coated Tubes”; CT) or microtiter plates, for example made of polystyrene, or of particles, for example magnetic particles while the other antibody is a Rest carries, which represents a directly detectable label or a selective link with a label allows and the detection of the formed sandwich structures. Also a delayed or subsequent immobilization using suitable solid phases is possible.
  • coated test tubes e.g., polystyrene; "Coated Tubes”; CT
  • microtiter plates for example made of polystyrene, or of particles, for example magnetic particles
  • Rest carries which represents a directly detectable label or a selective link with a label allows and the detection of the formed sandwich structures.
  • a delayed or subsequent immobilization using suitable solid phases is possible.
  • the inventive method also as a quick test to design.
  • the inventive method may further as a homogeneous Process be designed, in which the two Antibodies and the detected mid-proAM formed Sandwich complexes remain suspended in the liquid phase.
  • a homogeneous Process be designed, in which the two Antibodies and the detected mid-proAM formed Sandwich complexes remain suspended in the liquid phase.
  • Such techniques are particularly useful as fluorescence enhancers. or fluorescence quenching detection method capacities configurable.
  • a particular preferred such Method relates to the use of paired Detecting reagents, as described for example are disclosed in US-A-4,822,733, EP-B1-180492 or EP-B1-539477 and US-A-5,423,477 the cited prior art.
  • TRACE® Time Resolved Amplified Cryptate emission
  • KRYPTOR® technology refer the teachings of the o.g. Registrations implemented.
  • the determination method according to the invention particularly advantageous also in the context of a so-called multi-parameter diagnostics are performed can, both in the field of cardiac diagnostics as well as sepsis and cancer diagnostics. More here certain parameters are for example the cardiac parameters ANP, BNP, proANP or proBNP or sepsis parameters, e.g. are selected from the group consisting of anti-ganglioside antibodies, the proteins procalcitonin, CA 125, CA.
  • the invention will be described by a description of the Preparation of the Preferred Assay Components, Performance a preferred embodiment of an assay of Sandwich type and the use of such an assay obtained results of mid-proAM determinations in EDTA plasmas of controls, and of sepsis, heart and Cancer patients explained in more detail.
  • antisera the won starting with the fourth month after the immunization were the peptide-specific antibodies such as follows prepared.
  • the peptide columns were initially changed three times with each 10 ml of elution buffer (50 mM citric acid, pH 2.2) and Binding buffer (100 mM sodium phosphate, 0.1% Tween, pH 6.8) washed. 100 ml of the sheep antisera were over 0.2 microns filtered and mixed with the existing column material. For this purpose, the gel was quantitatively with 10 ml of binding buffer the column rinsed. The incubation was carried out overnight Room temperature while panning. The approaches were quantitative in empty columns (NAP 25, Pharmacia, deflated). The runs were discarded. Subsequently, with 250 ml binding buffer protein-free (protein content of the wash eluate ⁇ 0.02 A280 nm).
  • NAP-5 gel filtration column (Pharmacia) were 500 ⁇ l of the purified anti-SPCD19 antibody (see above) in 1 ml 100 mM potassium phosphate buffer (pH 8.0) according to instructions re-buffered. The protein concentration determination of the antibody solution gave a value of 1.5 mg / ml.
  • the chemiluminescent labeling of the antibody was 67 ⁇ l of the antibody solution with 10 ⁇ l of MA70-acridinium NHS ester (1 mg / ml; Company HOECHST Behring) and 15 minutes Room temperature incubated. Then 423 ⁇ l of 1 M glycine added and incubated for a further 10 minutes. Subsequently the labeling approach was via a NAP-5 gel filtration column (Pharmacia) in 1 ml of solvent A (50 mM potassium phosphate, 100 mM NaCl, pH 7.4) according to instructions and thereby freed of low molecular weight components.
  • solvent A 50 mM potassium phosphate, 100 mM NaCl, pH 7.4
  • a gel filtration HPLC was performed (Column: Waters Protein Pak SW300). The sample was applied and at a flow rate of 1 ml / min with eluent A chromatographed. With a flow-through photometer the wavelengths 280 nm and 368 nm were measured. The Absorbance ratio 368 nm / 280 nm as a measure of the degree of labeling of the antibody was 0.10 at the peak. The monomers Antibody-containing fractions (retention time 8-10 min) were collected and in 3 ml of 100 mM sodium phosphate, 150 mM NaCl, 5% Bovine Serum Albumin, 0.1% Sodium Azide, pH 7.4, added.
  • the standard material used was a chemically synthesized mid-proAM (SEQ ID NO: 3). This peptide was serialized in Horse normal serum (company SIGMA) diluted. The so produced Standards were concentrations according to the weight Attributed to peptide.
  • Test samples were EDTA plasmas of apparently healthy, of patients with sepsis and of patients with cardiac and with Cancers.
  • test tubes were 10 ul standards or samples as well 200 ⁇ l assay buffer containing 1 million RLU (relative light units) of the MA70-labeled anti-SPCD19 antibody, pipetted. It was incubated for two hours at 22 ° C with shaking. Then, 4 times with 1 ml of washing solution (0.1% Tween 20) per tube, drained and the am Tube bound chemiluminescence in a luminometer (BERTHOLD, LB952T, basic reagents BRAHMS AG).
  • RLU relative light units
  • the determinations were each 100 ⁇ l sample (resp. Standard) and 100 ⁇ l of tracer at 4 ° C in the with the SPCD19 peptide coated Polysorb tubes incubated overnight, then with 4 x 1 ml standard washing solution from the LUMItest® the applicant washed and then measured in the luminometer has been.
  • antibodies detected were three individual sepsis plasmas directly analytically via a C18 Reversed phase HPLC fractionated using a linear Acetonitrile gradient was eluted. There were 1 ml fractions collected and dried. The fractions were taken up in assay buffer and became SPCD19 immunoreactivity determined by the individual fractions. To was an anti-SPCD19 antibody (see above under 3.) to the Walls of a Polysorb tube immobilized, and the competition of sample (fraction) and luminescence-labeled SPCD19 around this antibody was determined.
  • Molar mass of the isolated analyte has a value of about 5146 Dalton determined. This value corresponds to the molecular weight of a proAM fragment containing the amino acids of positions 45-92, i.e. of mid-proAM, contains (the theoretical value is, assuming that the two existing methionine residues oxidized, 5146.72 daltons).
  • a determination of the mid-proAM is not subject to any known Limitations due to the existence of a binding protein, fragmentation and weak concentration dynamics.
  • the analyte mid-proAM also has good stability, i.e. a very small loss of immunoreactivity Storage at room temperature, which is for diagnostic routine conditions represents a great practical advantage.

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Claims (18)

  1. Procédé de détermination in vitro de l'immunoréactivité à l'adrénomédulline dans des liquides biologiques dans un but de diagnostic, caractérisé en ce que l'on mesure le peptide partiel de la région médiane (mid-proAM; SEQ ID NO:3) de la proadrénomédulline, qui comprend les acides aminés (45-92) de la préproadrénomédulline complète (pré-proAM; SED ID NO:1).
  2. Procédé selon la revendication 1, caractérisé en ce que l'on mesure la mid-proAM dans les liquides biologiques au moyen d'une immunodétermination qui fonctionne avec au moins un anticorps marqué qui reconnaít spécifiquement une séquence de mid-proAM.
  3. Procédé selon la revendication 2, caractérisé en ce que l'immunodétermination est une détermination au moyen d'un compétiteur des analytes qui est lié à une phase solide et d'un anticorps marqué (test SPALT) ou est un test par sandwich (test immunologique bilatéral), dans lequel on utilise au moins deux anticorps qui se lient spécifiquement à différentes séquences partielles de la mid-proAM (SEQ ID NO:3).
  4. Procédé selon l'une des revendications 1 à 3, caractérisé en ce que l'on détermine la mid-proAM en circulation (SEQ ID NO:3) et en ce que le liquide biologique est un plasma.
  5. Procédé selon la revendication 3, caractérisé en ce que les deux anticorps se lient à une zone de la mid-proAM qui s'étend de l'acide aminé 60 jusqu'à l'acide aminé 94 de la pré-proAM.
  6. Procédé selon l'une des revendications 1 à 5, caractérisé en ce que le ou les anticorps sont des anticorps monoclonaux et/ou polyclonaux.
  7. Procédé selon l'une des revendications 1 à 6, caractérisé en ce que les deux anticorps sont des anticorps polyclonaux purifiés par affinité.
  8. Procédé selon l'une des revendications 1 à 7, caractérisé en ce que l'un des anticorps est obtenu par immunisation d'un animal au moyen d'un antigène qui contient une séquence peptidique de synthèse qui comprend les acides aminés 69 à 86 de la pré-proAM (SEQ ID NO:4), l'autre anticorps étant obtenu par immunisation au moyen d'un antigène qui comprend une séquence peptidique de synthèse qui comprend les acides aminés 83 à 94 de la pré-proAM (SEQ ID NO:5).
  9. Procédé selon l'une des revendications 1 à 8, caractérisé en ce que l'un des anticorps est marqué et l'autre anticorps est lié à une phase solide ou peut être lié sélectivement à une phase solide.
  10. Procédé selon l'une des revendications 1 à 8, caractérisé en ce que tant le premier que le deuxième anticorps sont en dispersion dans le mélange réactionnel liquide et en ce qu'un premier composant de marquage est lié au premier anticorps et fait partie d'un système de marquage basé sur l'atténuation ou sur le renforcement de la fluorescence ou de la chimioluminescence et en ce que le deuxième composant de marquage de ce système de marquage est lié au deuxième anticorps, de telle sorte qu'une fois que les deux anticorps se sont liés à la mid-proAM à déceler, un signal mesurable est créé et permet de détecter le complexe sandwich formé dans la solution de mesure.
  11. Procédé selon la revendication 10, caractérisé en ce que le système de marquage comprend des cryptates de terre rare ou des chélates de terre rare en combinaison avec un colorant fluorescent ou un colorant chimioluminescent, en particulier du type cyanine.
  12. Procédé selon l'une des revendications 1 à 11, caractérisé en ce qu'il est utilisé pour diagnostiquer la septicémie, en déterminer le degré de gravité, faire des pronostics et contrôler la thérapie qui accompagne l'évolution de la maladie.
  13. Procédé selon la revendication 12, caractérisé en ce qu'il est exécuté dans le cadre d'une détermination de plusieurs paramètres, dans laquelle on détermine en même temps au moins un autre paramètre pertinent pour le diagnostic de la septicémie.
  14. Procédé selon la revendication 13, caractérisé en ce que le ou les autres paramètres pertinents pour le diagnostic de la septicémie sont sélectionnés dans le groupe constitué des anticorps antigangliosides, des protéines procalcitonine, CA 125, CA 19-9, S100B et S100A, des fragments solubles de cytokératine et en particulier des fragments solubles de CYFRA 21, de TPS et/ou de cytokératine-1 (sCYIF), des peptides inflammine et CHP, d'autres prohormones peptidiques, de la glycine-N-acyltransférase (GNAT), de la phosphate carbamoyle synthétase 1 de (CPS 1) et de la protéine C-réactive (CRP) ou de fragments de celle-ci.
  15. Procédé selon l'une des revendications 1 à 11, caractérisé en ce qu'il est utilisé en diagnostic cardiologique.
  16. Procédé selon la revendication 15, caractérisé en ce qu'il est exécuté dans le cadre de la détermination de plusieurs paramètres dans laquelle on détermine en même temps d'autres paramètres pertinents pour le diagnostic cardiologique.
  17. Procédé selon l'un des revendications 1 à 11, caractérisé en ce qu'on l'utilise dans le domaine du diagnostic du cancer.
  18. Procédé selon la revendication 17, caractérisé en ce qu'il est exécuté dans le cadre de la détermination de plusieurs paramètres dans laquelle on détermine en même temps d'autres paramètres pertinents pour le diagnostic du cancer.
EP04700013A 2003-04-10 2004-01-29 Mise en evidence d'un peptide partiel proadrenomedulline a region moyenne dans des liquides biologiques, a des fins diagnostiques et dosages immunologiques utilises pour effectuer une mise en evidence de ce type Expired - Lifetime EP1488209B1 (fr)

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DE10316583 2003-04-10
DE10316583A DE10316583A1 (de) 2003-04-10 2003-04-10 Bestimmung eines midregionalen Proadrenomedullin-Teilpeptids in biologischen Flüssigkeiten zu diagnostischen Zwecken, sowie Immunoassays für die Durchführung einer solchen Bestimmung
PCT/EP2004/000806 WO2004090546A1 (fr) 2003-04-10 2004-01-29 Mise en evidence d'un peptide partiel proadrenomedulline a region moyenne dans des liquides biologiques, a des fins diagnostiques et dosages immunologiques utilises pour effectuer une mise en evidence de ce type

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EP1488209B1 true EP1488209B1 (fr) 2005-12-07

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DE102008007218A1 (de) 2008-02-01 2009-08-06 B.R.A.H.M.S Aktiengesellschaft Verfahren zur Indentifizierung von therapiebedürftigen Patienten und zur präventiven Behandlung derartiger Patienten mit leichten kognitiven Störungen
US20100209433A1 (en) * 2005-12-01 2010-08-19 B.R.A.H.M.S Aktiengesellschaft Methods for the diagnosis and for the treatment of critically ill patients with endothelin, endothelin agonists and adrenomedullin antagonists
US8436135B2 (en) 2006-12-20 2013-05-07 Brahms Gmbh Diagnosis and risk stratification by determining the marker CT-proADM
EP3438668A1 (fr) 2017-08-04 2019-02-06 B.R.A.H.M.S GmbH Diagnostic et stratification des risques d'infections fongiques
EP3502706A1 (fr) 2017-12-20 2019-06-26 B.R.A.H.M.S GmbH Workflow pour l'évaluation du risque et la gestion de patients à l'aide de la procalcitonine et de la proadrénoméduline midrégionale
WO2020201078A1 (fr) 2019-03-29 2020-10-08 B.R.A.H.M.S Gmbh Prescription de gestion de patient à distance basée sur des biomarqueurs
US11327082B2 (en) 2017-09-13 2022-05-10 B.R.A.H.M.S Gmbh Proadrenomedullin as a marker for abnormal platelet levels

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US20070212742A1 (en) 2007-09-13
WO2004090546A1 (fr) 2004-10-21
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JP2010210644A (ja) 2010-09-24
MXPA05010827A (es) 2006-03-09
US20180143190A1 (en) 2018-05-24
DE502004000166D1 (de) 2006-01-12
ATE312342T1 (de) 2005-12-15
JP4602321B2 (ja) 2010-12-22
DE10316583A1 (de) 2004-10-28
US20140322822A1 (en) 2014-10-30
HK1089232A1 (en) 2006-11-24
US9885709B2 (en) 2018-02-06
CN1759319B (zh) 2011-08-10
EP1488209A1 (fr) 2004-12-22
US9541549B2 (en) 2017-01-10
ES2250959T3 (es) 2006-04-16
JP5021791B2 (ja) 2012-09-12

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